Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis

Naotaka Tsutsumi; Zahra Masoumi; Sophie C James; Julie A Tucker; Hauke Winkelmann; William Grey; Lora K Picton; Lucie Moss; Steven C Wilson; Nathanael A Caveney; Kevin M Jude; Cornelius Gati; Jacob Piehler; Ian S Hitchcock; K Christopher Garcia

doi:10.1016/j.cell.2023.07.037

Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis

Cell. 2023 Sep 14;186(19):4189-4203.e22. doi: 10.1016/j.cell.2023.07.037. Epub 2023 Aug 25.

Authors

Affiliations

¹ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan. Electronic address: ntsutsumi@okayama-u.ac.jp.
² York Biomedical Research Institute, Department of Biology, University of York, Heslington, York YO10 5DD, UK.
³ Department of Biology/Chemistry and Center of Cellular Nanoanalytics, Osnabrück University, 49076 Osnabrück, Germany.
⁴ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Biosciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA 94025, USA.
⁸ York Biomedical Research Institute, Department of Biology, University of York, Heslington, York YO10 5DD, UK. Electronic address: ian.hitchcock@york.ac.uk.
⁹ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kcgarcia@stanford.edu.

PMID: 37633268
PMCID: PMC10528194 (available on 2024-09-14)
DOI: 10.1016/j.cell.2023.07.037

Abstract

Thrombopoietin (THPO or TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Here, we report the 3.4 Å resolution cryoelectron microscopy structure of the extracellular TPO-TPO receptor (TpoR or MPL) signaling complex, revealing the basis for homodimeric MPL activation and providing a structural rationalization for genetic loss-of-function thrombocytopenia mutations. The structure guided the engineering of TPO variants (TPO^mod) with a spectrum of signaling activities, from neutral antagonists to partial- and super-agonists. Partial agonist TPO^mod decoupled JAK/STAT from ERK/AKT/CREB activation, driving a bias for megakaryopoiesis and platelet production without causing significant HSC expansion in mice and showing superior maintenance of human HSCs in vitro. These data demonstrate the functional uncoupling of the two primary roles of TPO, highlighting the potential utility of TPO^mod in hematology research and clinical HSC transplantation.

Keywords: JAK-STAT; TpoR; c-MPL; cryo-EM; hematopoiesis; ligand engineering; mTOR; signaling; structure; thrombopoietin.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Cycle
Cryoelectron Microscopy
DNA Methylation
Humans
Mice
Receptors, Thrombopoietin* / genetics
Thrombopoiesis
Thrombopoietin*

Substances

MPL protein, human
Receptors, Thrombopoietin
Thrombopoietin

Abstract

Publication types

MeSH terms

Substances

Grants and funding